Abstract
Alternaria toxins are considered as emerging mycotoxins, however their toxicity has not been fully evaluated in humans. Alternariol (AOH), the most prevalent Alternaria mycotoxin, was previously reported to be genotoxic and to affect hormonal balance in cells; however, its direct molecular mechanism is not known. The imbalance in androgen/estrogen ratio as well as chronic inflammation are postulated as factors in prostate diseases. The environmental agents affecting the hormonal balance might participate in prostate carcinogenesis. Thus, this study evaluated the effect of two doses of AOH on prostate epithelial cells. We observed that AOH in a dose of 10 µM induces oxidative stress, DNA damage and cell cycle arrest and that this effect is partially mediated by estrogen receptor β (ERβ) whereas the lower tested dose of AOH (0.1 µM) induces only oxidative stress in cells. The modulation of nuclear erythroid-related factor 2 (Nrf2) was observed in response to the higher dose of AOH. The use of selective estrogen receptor β (ERβ) inhibitor PHTPP revealed that AOH-induced oxidative stress in both tested doses is partially dependent on activation of ERβ, but lack of its activation did not protect cells against AOH-induced ROS production or DNA-damaging effect in case of higher dose of AOH (10 µM). Taken together, this is the first study reporting that AOH might affect basic processes in normal prostate epithelial cells associated with benign and malignant changes in prostate tissue.
Highlights
Mycotoxins, as the toxic metabolites of fungi, are present in every day human diets, both in processed as well as unprocessed food
It was observed that AOH in a dose range between 10 and 100 μM significantly influenced the viability of prostate epithelial cells (*** p < 0.001), while concentrations below 10 μM caused no effect, both after 24 and 48 h
The results presented here show that AOH induced oxidative stress in PNT1A cells is associated with DNA damage (Figure 3), cell cycle arrest in G2/M cell cycle phase (Figure 4) and that effect is partially caused by activation of estrogen receptor β (ERβ) confirming a previous statement that AOH possesses estrogenic effect in cells [9]
Summary
Mycotoxins, as the toxic metabolites of fungi, are present in every day human diets, both in processed as well as unprocessed food. Alternariol (AOH) is one of the most abundant mycotoxins produced by Alternaria spp.—a commonly found black mold, affecting food products and buildings [2]. Besides genotoxicity as a main concern, AOH in a dose of 10 μM was reported to modulate the immune response in cells [7]. It acts as an endocrine disruptor via modulation of androgen receptor (AR) signaling with the half maximal effective concentration (EC50) of 269.4 μM [8]. Data are not consistent though—a mixture of different Alternaria mycotoxins was reported to trigger an anti-estrogenic rather than estrogenic in endometrial cancer cell line Ishikawa treated with AOH (0.1–50 μg/mL) and 1 nM estradiol (E2) [10]. It is highly possible that the estrogenic effect of AOH might be cell typedependent and still it has not been evaluated in prostate epithelial cells
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